Dihydrophenazinecarboxylic acid derivatives

ABSTRACT

Dihydrophenazinecarboxylic acid derivatives of the formula (I) wherein R 1  represents hydrogen, linear or branched alkyl, etc., each of R 2  and R 3  represents hydrogen, 3-methyl-2-butenyl, etc., and each of R 4  and R 5  represents hydrogen, alkyl, alkenyl, aralkyl, aryl, hydroxyl, alkoxy, aryloxy, aralkyloxy, halogen, nitro, cyano, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, arylcarbonyl, etc., provided that there is no case that both of R 4  and R 5  are hydrogen. The dihydrophenazinecarboxylic acid derivatives are excellent in the inhibition of glutamic acid toxicity. ##STR1##

This application is a 371 of PCT/P97/03674 Oct. 14, 1997.

FIELD OF THE INVENTION

This invention relates to dihydrophenazinecarboxylic acid derivatives.More particularly, the invention relates to dihydrophenazinecarboxylicacid derivatives having the below-mentioned formula (I) or (III), and aninhibitory agent of glutamic acid toxicity which contains adihydrophenazinecarboxylic acid derivative having the below-mentionedformula (I), (III) or (V) as an active ingredient.

BACKGROUND OF THE INVENTION

It is known that glutamic acid which is one of natural amino acids hastoxicity to neurocyte (Akaike Akinori, Folia Pharmacol. Jpn. 103,193-201 (1994), etc.). A substance inhibiting glutamic acid toxicity toneurocyte is employable as a brain metabolism activating agent or abrain metabolism improving agent.

Seto et al. reported that sugar moiety-containingdihydrophenazinecarboxylic acid derivatives represented by thebelow-mentioned formulas (A) and (B) [aestivophoenins A & B] which wereisolated from actinomyces belonging to genus Streptomyces inhibitglutamic acid toxicity and shows antioxidant property: J. Antibiotics,48, 1378 (1995) and PCT WO96/22996. ##STR2##

Further, a dihydrophenazinecarboxylic acid derivative having no sugarmoiety which is represented by the following formula (C): ##STR3## isknown {Ann. Chim. [13], 1, 115(1956)].

Also known is a compound of the following formula (D) which has no sugarmoiety (benthophoenin): ##STR4## and its methyl ester. These compoundsare reported to be employable as a free radical scavenger(anti-oxidant). [J. Nat. Prod., 56, 1255(1993)].

Also known is a compound of the following formula (E) which has no sugarmoiety: ##STR5## wherein R represents hydrogen, methyl or nitro [Helv.Chim. Acta, 52, 322(1969)].

Also known is a compound of the following formula (F) which has no sugarmoiety: ##STR6## [J. Gen. Microbiol., 104, 299(1978)].

As for the above-mentioned dihydrophenazinecarboxylic acid derivativeshaving no sugar moiety, the publications give no description concerninginhibition of glutamic acid toxicity.

The compound having the aforementioned formula (D) is obtained only fromthe mycelium of Streptomyces prunicolor.

The compounds having the aforementioned formulas (A) and (B) which arereported to show inhibition of glutamic acid toxicity are naturalproducts. It is not expected to produce enough amounts of thesecompounds by culture. Further, it is difficult to prepare thesecompounds by organic synthetic methods because the compounds haveL-rhamnose residue in the molecular structure. Until now, no reportshave been given on total synthesis of these compounds or their analogs.

Accordingly, it is desired to provide dihydrophenazinecarboxylic acidderivatives which show inhibition of glutamic acid toxicity and whichare easily synthesized.

DISCLOSURE OF THE INVENTION

The inventors studied on compounds showing inhibition of glutamic acidtoxicity and discovered that dihydrophenazinecarboxylic acid derivativeshaving no sugar moiety and being represented by the under-mentionedformula (I), (III) or (V) shows excellent inhibitory activity againstglutamic acid toxicity. The present invention has been made on thediscovery.

The present invention resides in a dihydrophenazinecarboxylic acidderivative having the formula (I): ##STR7## in which

R¹ represents a hydrogen atom, a linear or branched chain alkyl group,an aralkyl group or an aryl group;

each of R² and R³ is the same or different from each other andrepresents a hydrogen atom, an alkenyl group having 2 to 5 carbon atoms,an alkyl group, an aralkyl group, an aryl group, or a group representedby the formula (II): ##STR8## wherein each of R⁶ and R⁷ is the same ordifferent from each other and represents a hydrogen atom, a linear orbranched chain alkyl group, an aralkyl group or an aryl group, or R⁶ andR⁷ are combined together to form a nitrogen atom-containing 5- to7-membered ring in conjunction with the adjacent nitrogen atom, and m is2, 3 or 4;

each of R⁴ and R⁵ is the same or different from each other andrepresents a hydrogen atom, a linear or branched chain alkyl group, analkenyl group, an alkynyl group, an aralkyl group, an aryl group, ahydroxyl group, an alkoxy group, an aryloxy group, an aralkyloxy group,a halogen atom, a nitro group, a cyano group, an alkylsulfonyl group, anarylsulfonyl group, an alkylcarbonyl group, an arylcarbonyl group, anaralkylcarbonyl group, a halo-alkyl group, a halo-alkoxy group, or agroup represented by --NR⁸ R⁹ or --SO₂ NR¹⁰ R¹¹ wherein each of R⁸ andR⁹ is the same or different from each other and represents a hydrogenatom, a linear or branched chain alkyl group, an aralkyl group or anaryl group, and each of R¹⁰ and R¹¹ is the same or different from eachother and represents a hydrogen atom, a linear or branched chain alkylgroup, an aralkyl group or an aryl group; provided that there is no casethat R⁴ and R⁵ both are hydrogen atoms.

The invention further resides in a dihydrophenazinecarboxylic acidderivative having the formula (III): ##STR9## in which

R²¹ represents a hydrogen atom, a linear or branched chain alkyl group,an aralkyl group or an aryl group;

each of R²² and R²³ is the same or different from each other andrepresents a hydrogen atom, an alkenyl group having 2 to 5 carbon atoms,an alkyl group, an aralkyl group, an aryl group, or a group representedby the formula (IV): ##STR10## wherein each of R²⁶ and R²⁷ is the sameor different from each other and represents a hydrogen atom, a linear orbranched chain alkyl group, an aralkyl group or an aryl group, or R²⁶and R²⁷ are combined together to form a nitrogen atom-containing 5- to7-membered ring in conjunction with the adjacent nitrogen atom, and n is2, 3 or 4;

each of R²⁰, R²⁴ and R²⁵ is the same or different from each other andrepresents a hydrogen atom, a linear or branched chain alkyl group, analkenyl group, an alkynyl group, an aralkyl group, an aryl group, ahydroxyl group, an alkoxy group, an aryloxy group, an aralkyloxy group,a halogen atom, a nitro group, a cyano group, an alkylsulfonyl group, anarylsulfonyl group, a halo-alkyl group, a halo-alkoxy group, or a grouprepresented by --NR²⁸ R²⁹ or --SO₂ NR³⁰ R³¹ wherein each of R²⁸ and R²⁹is the same or different from each other and represents a hydrogen atom,a linear or branched chain alkyl group, an aralkyl group or an arylgroup, and each of R³⁰ and R³¹ is the same or different from each otherand represents a hydrogen atom, a linear or branched chain alkyl group,an aralkyl group or an aryl group.

The invention furthermore resides in an inhibitory agent of of glutamicacid toxicity containing an effective amount of adihydrophenazinecarboxylic acid derivative of the aforementioned formula(I) or (III) [active ingredient].

The invention furthermore resides in an inhibitory agent for inhibitionof glutamic acid toxicity containing an effective amount of adihydrophenazinecarboxylic acid derivative of the following formula (V):##STR11## in which

R⁴¹ represents a hydrogen atom, a linear or branched chain alkyl group,an aralkyl group or an aryl group;

each of R⁴² and R⁴³ is the same or different from each other andrepresents a hydrogen atom, an alkyl group, an aralkyl group, an arylgroup, an alkenyl group having 2 to 5 carbon atoms, or a grouprepresented by the formula (VI): ##STR12## wherein each of R⁴⁶ and R⁴⁷is the same or different from each other and represents a hydrogen atom,a linear or branched chain alkyl group, an aralkyl group or an arylgroup, or R⁴⁶ and R⁴⁷ are combined together to form a nitrogenatom-containing 5- to 7-membered ring in conjunction with the adjacentnitrogen atom, and p is 2, 3 or 4;

each of R⁴⁴ and R⁴⁵ is the same or different from each other andrepresents a hydrogen atom, a linear or branched chain alkyl group, analkenyl group, an alkynyl group, an aralkyl group, an aryl group, ahydroxyl group, an alkoxy group, an aryloxy group, an aralkyloxy group,a halogen atom, a nitro group, a cyano group, an alkylsulfonyl group, anarylsulfonyl group, an alkylcarbonyl group, an arylcarbonyl group, anaralkylcarbonyl group, a halo-alkyl group, a halo-alkoxy group, acarboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, aformyl group, or a group represented by --NR⁴⁸ R⁴⁹ or --SO₂ NR⁵⁰ R⁵¹wherein each of R⁴⁸ and R⁴⁹ is the same or different from each other andrepresents a hydrogen atom, a linear or branched chain alkyl group, anaralkyl group or an aryl group, and each of R⁵⁰ and R⁵¹ is the same ordifferent from each other and represents a hydrogen atom, a linear orbranched chain alkyl group, an aralkyl group or an aryl group.

PREFERRED EMBODIMENTS OF THE INVENTION

The dihydrophenazinecarboxylic acid derivative of the formula (I) isdescribed in more detail.

In the formula (I), R¹ can be a hydrogen atom, a linear or branchedchain alkyl group having 1 to 8 carbon atoms (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, or tert-butyl), an aralkyl grouphaving an alkylene moiety of 1 to 4 carbon atoms (e.g., benzyl orphenethyl), or an aryl group (e.g., phenyl or naphthyl).

Each of R² and R³ is the same or different from each other and can be ahydrogen atom, an alkenyl group having 2 to 5 carbon atoms (e.g., allylor 3-methyl-2-butenyl), an alkyl group having 1 to 8 carbon atoms (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl), anaralkyl group having an alkylene moiety of 1 to 4 carbon atoms (e.g.,benzyl or phenethyl), an aryl group (e.g., phenyl or naphthyl), or agroup represented by the formula (II): ##STR13## (wherein each of R⁶, R⁷and m has the aforementioned meaning).

In the group represented by the formula (II), each of R⁶ and R⁷ is thesame or different from each other, and can be a hydrogen atom, an alkylgroup having 1 to 8 carbon atoms (e.g., methyl, ethyl, propyl,isopropyl, butyl, or isobutyl), an aralkyl group having an alkylenemoiety of 1 to 4 carbon atoms (e.g., benzyl or phenethyl), an aryl group(e.g., phenyl or naphthyl). Otherwise, R⁶ and R⁷ are combined togetherto form a nitrogen atom-containing 5- to 7-membered ring (e.g.,pyrrolidine or piperidine) in conjunction with the nitrogen atom towhich R⁶ and R⁷ are attached. m is 2, 3 or 4.

Each of R⁴ and R⁵ is the same or different from each other and can be ahydrogen atom, a linear or branched chain alkyl group having 1 to 8carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,or tertbutyl), an alkenyl group having 2 to 8 carbon atoms (e.g., vinyl,allyl or 3-methyl-2-butenyl), an alkynyl group having 2 to 8 carbonatoms (e.g., propynyl), an aralkyl group having an alkylene moiety of 1to 4 carbon atoms (e.g., benzyl or phenethyl), an aryl group (e.g.,phenyl or naphthyl), a hydroxyl group, an alkoxy group having 1 to 8carbon atoms (e.g., methoxy, ethoxy or propoxy), an aryloxy group (e.g.,phenyloxy), an aralkyloxy group having an alkylene moiety of 1 to 4carbon atoms (e.g., benzyloxy or phenethyloxy), a halogen atom (e.g.,fluorine, chlorine or bromine), a nitro group, a cyano group, analkylsulfonyl group having an alkyl moiety of 1 to 8 carbon atoms (e.g.,methylsulfonyl), an arylsulfonyl group (e.g., benzenesulfonyl), analkylcarbonyl group having an alkyl moiety of 1 to 8 carbon atoms (e.g.,acetyl or propionyl), an arylcarbonyl group (e.g., benzoyl), anaralkylcarbonyl group (e.g., benzylcarbonyl), a halo-alkyl group having1 to 8 carbon atoms and 1 to 3 halogen atoms such as chlorine, fluorineor bromine (e.g., chloromethyl, chloroethyl, or trifluoromethyl), ahalo-alkoxy group having 1 to 8 carbon atoms and 1 to 3 halogen atomssuch as chlorine, fluorine or bromine (e.g., 2-chloroethoxy ortrifluoromethoxy), or a group represented by --NR⁸ R⁹ or --SO₂ NR¹⁰ R¹¹.

In the above-mentioned formula, each of R⁸ and R⁹ is the same ordifferent from each other and can be a hydrogen atom, a linear orbranched chain alkyl group having 1 to 8 carbon atoms (e.g., methyl,ethyl, propyl, isopropyl, butyl, or isobutyl), an aralkyl group havingan alkylene moiety of 1 to 4 carbon atoms (e.g., benzyl or phenethyl) oran aryl group (e.g., phenyl or naphthyl).

Each of R¹⁰ and R¹¹ is the same or different from each other and can bea hydrogen atom, a linear or branched chain alkyl group having 1 to 8carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, orisobutyl), an aralkyl group having an alkylene moiety of 1 to 4 carbonatoms (e.g., benzyl or phenethyl) or an aryl group (e.g., phenyl ornaphthyl).

The dihydrophenazinecarboxylic acid derivative of the formula (III) isdescribed in more detail.

R²¹ of the formula (III) has the same meaning as that of R¹ of theformula (I), and each of R²² and R²³ of the formula (III) has the samemeaning as that of each of R² and R³ of the formula (I), respectively.Each of R²⁶ and R²⁷ of the formula (III) [formula (IV)] has the samemeaning as that of each of R⁶ and R⁷ of the formula (I) [formula (II)],respectively. Each of R²⁸ and R²⁹ of the formula (III) has the samemeaning as that of each of R⁸ and R⁹ of the formula (I), respectively,and each of R³⁰ and R³¹ of the formula (III) has the same meaning asthat of each of R¹⁰ and R¹¹ of the formula (I), respectively. Each ofR²⁰, R²⁴ and R²⁵ of the formula (III) has the same meaning as that of R⁴or R⁵ of the formula (I), under the condition that the alkylcarbonylgroup, arylcarbonyl group, and aralkylcarbonyl group are excluded.

The dihydrophenazinecarboxylic acid derivative of the formula (V) isdescribed in more detail.

R⁴¹ of the formula (V) has the same meaning as that of R¹ of the formula(I), and each of R⁴² and R⁴³ of the formula (V) has the same meaning asthat of each of R² and R³ of the formula (I), respectively. Each of R⁴⁴and R⁴⁵ of the formula (V) has the same meaning as that of R⁴ or R⁵ ofthe formula (I) or can be a carboxy group or an alkoxycarbonyl grouphaving 2 to 8 carbon atoms (e.g., methoxycarbonyl, or ethoxycarbonyl),an aralkyloxycarbonyl group (e.g., benzyloxycarbonyl), or a formylgroup.

Each of R⁴⁶ and R⁴⁷ of the formula (V) [formula (VI)] has the samemeaning as that of each of R⁶ and R⁷ of the formula (I) [formula (II)],respectively. Each of R⁴⁸ and R⁴⁹ of the formula (V) has the samemeaning as that of each of R⁸ and R⁹ of the formula (I), respectively,and each of R⁵⁰ and R⁵ l of the formula (V) has the same meaning as thatof each of R¹⁰ and R¹¹ of the formula (I), respectively.

It should be noted that each of R⁴ and R⁵ of the formula (I), each ofR²⁰, R²⁴ and R²⁵ of the formula (III), and each of R⁴⁴ and R⁴⁵ of theformula (V) can be single or plural.

The present inventors have found that a dihydrophenazinecarboxylic acidderivative of the formula (I) in which both of R⁴ and R⁵ are hydrogenatoms is easily oxidized under atmospheric conditions and is thereforeunstable. For instance, the inventors have ascertained that ethyl5,10-dihydro-1-phenazinecarboxylate is unstable at room temperature.

For the above-mentioned reason, each of R⁴ and R⁵ of the formula (I) andeach of R⁴⁴ and R⁴⁵ of the formula (V) preferably is anelectron-attracting group such as nitro or benzoyl.

The aromatic rings contained in the aralkyl group, aryl group, aryloxygroup, aralkyloxy group, arylsulfonyl group, arylcarbonyl group,aralkylcarbonyl group, and aralkyloxy group of the substituent groups ofthe formulas (I), (III) and (V) can have substituent groups. Thearomatic rings can be contained in the following groups:

aralkyl and aryl groups of R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ ofthe formula (I);

aralkyl, aryl, aryloxy, aralkyloxy, arylsulfonyl, arylcarbonyl andaralkylcarbonyl groups of R⁴ and R⁵ of the formula (I);

aralkyl and aryl groups of R²¹, R²², R²³ R²⁶, R²⁷, R²⁸ R²⁹, R³⁰ and R³¹of the formula (III);

aralkyl, aryl, aryloxy, aralkyloxy and arylsulfonyl groups of R²⁰, R²⁴and R²⁵ of the formula (III);

aralkyl and aryl groups of R⁴¹, R⁴², R⁴³, R⁴⁶, R⁴⁷ R⁴⁸ R⁴⁹, R⁵⁰ and R⁵¹of the formula (V); and

aralkyl, aryl, aryloxy, aralkyloxy, arylsulfonyl, arylcarbonyl,aralkylcarbonyl and aralkyloxycarbonyl groups of R⁴⁴ and R⁴⁵ of theformula (V).

Examples of the substituent groups which can be attached to the aromaticrings include a lower alkyl group having 1 to 6 carbon atoms (e.g.,methyl, ethyl, or propyl), a lower alkoxy group having 1 to 6 carbonatoms (e.g., methoxy, ethoxy, or propoxy), a halogen atom (e.g.,chlorine or fluorine), a lower alkyl group having 1 to 6 carbon atomsand 1 to 3 halogen atoms (e.g., trifluoromethyl), and a lower alkoxygroup having 1 to 6 carbon atoms and 1 to 3 halogen atoms (e.g.,trifluoromethoxy).

The linear or branched chain alkyl groups for R¹ of the formula (I), R²¹of the formula (III) and R⁴¹ of the formula (V) can contain an aminogroup (NH₂), an alkylamino group having 1 to 6 carbon atoms (e.g.,ethylamino), an aralkylamino having an alkyl moiety of 1 to 4 carbonatoms (e.g., benzylamino), a dialkylamino group having two alkylmoieties (each alkyl has 1 to 6 carbon atoms) (e.g., dimethylamino ordiethylamino), a cyclic amino group (e.g., piperidino or morpholino),and a diaralkylamino group having two aralkyl moieties (each alkyl has 1to 4 carbon atoms) (e.g., dibenzylamino).

The dihydrophenazinecarboxylic acid derivative of the formula (I) can beprepared by the following synthesis route: ##STR14##

In the above-illustrated formulas, each of X¹ and X² represents aleaving group such as chlorine, bromine, iodine, mesyloxy, or tosyloxy;and each of R¹, R², R³, R⁴ and R⁵ has the same meanings as mentionedhereinbefore, provided that there is no case where both of R² and R³ arehydrogen atoms.

In the above-illustrated synthesis route, a compound of the formula (b)can be obtained by reducing a compound of the formula (a) or (a') in aninert solvent such as a mixture of ethanol and water at a temperaturefrom room temperature to the boiling point of the solvent in thepresence of a reducing agent such as sodium hydrosulfite.

When a compound of the formula (a') is employed as the startingcompound, a compound of the formula (b) can be obtained by catalyticreduction using a Raney nickel catalyst, a palladium/carbon catalyst, ora rhodium catalyst in an inert solvent such as ethanol, methanol,acetone or methylene chloride. Otherwise, the compound of the formula(b) can be obtained by reducing the compound of the formula (a') byhydrazine and palladium/carbon in an inert solvent such as methanol orethanol.

A compound of the formula (c) can be obtained by reacting the compoundof the formula (b) with a compound of the formula R³ X¹ (R³ and X¹ isthe same as above) such as an alkyl halide in an inert solvent such asacetone, 2-butanone, 4-methyl-2-pentanone, or tetrahydrofuran in thepresence of a base such as anhydrous potassium carbonate, anhydroussodium carbonate, or sodium hydride.

A compound of the formula (d) can be obtained from the above-mentionedcompound of the formula (b) in the same manner as described in thepreparation of the compound of the formula (c).

The compound of the formula (b), (c) or (d) can be subjected totransesterification to give a different alkyl ester.

The starting compound of the formula (a) can be obtained in the samemanner as that described, for instance, in J. Chem. Soc., Perkin Trans.1, 1354(1974) or U.S. Pat. No. 3,615,494.

The compound of the formula (a') can be obtained in the same manner asthat described, for instance, in J. Med. Chem., 30, 843(1987) or Synth.Commun., 17, 1171(1987).

The dihydrophenazinecarboxylic acid derivative of the formula (III) or(V) can be obtained in the same manner as that described above for theabove-mentioned preparation of the dihydrophenazinecarboxylic acidderivative of the formula (I).

The dihydrophenazinecarboxylic acid derivative of the formula (I),(III), or (V) can be employed in the form of a pharmacologicallyacceptable salt with a base such as an alkali metal (e.g., sodium orpotassium) or an organic amine (e.g., methylamine) or with an acid suchas a mineral acid (e.g., hydrochloric acid or hydrobromic acid) or anorganic acid (e.g., fumaric acid or acetic acid).

Representative examples of the dihydrophenazinecarboxylic acidderivatives of the formula (III) are set forth in Tables 1 and 2, inwhich "Position" means the position of benzoyl substituent.

                  TABLE 1                                                         ______________________________________                                        R.sup.21                                                                            R.sup.22                                                                             R.sup.23   R.sup.24                                                                           R.sup.25                                                                           Position                                                                            R.sup.20                              ______________________________________                                        Et    H      H          H    H    7     H                                       H H 3-Me-2-Bute H H 7 H                                                       Me H 3-Me-2-Bute H H 7 H                                                      Et H 3-Me-2-Bute H H 7 H                                                      i-Pr H 3-Me-2-Bute H H 7 H                                                    t-Bu H 3-Me-2-Bute H H 7 H                                                    Benz H 3-Me-2-Bute H H 7 H                                                    Et H 3-Me-2-Bute H H 7 3-NO.sub.2                                             Benz H 3-Me-2-Bute H H 8 3-F                                                  Et H Me H H 7 H                                                               Et H Me H H 7 3-F                                                             Et H Me H H 7 4-Cl                                                            t-Bu H Me H H 7 4-MeO                                                         Et H Me H H 7 3,4-diMeO                                                       Et H Me H H 9 4-Cl                                                            Et H i-Bu H H 6 4-F                                                           Et H Benz H H 7 H                                                             Et H 3-(diMeAm)Pr H H 7 H                                                   ______________________________________                                    

                                      TABLE 2                                     __________________________________________________________________________    R.sup.21                                                                             R.sup.22                                                                            R.sup.23                                                                             R.sup.24                                                                            R.sup.25                                                                            Position                                                                          R.sup.20                                  __________________________________________________________________________    Et     H     2-(1-Pyrro)Et                                                                        H     H     8   H                                           Et 3-Me-2-Bute 3-Me-2-Bute H H 7 H                                            Et Me 3-Me-2-Bute H H 7 H                                                     Et Me Benz H H 7 H                                                            i-Bu Benz 3-Me-2-Bute H H 7 4-Cl                                              Et H 3-Me-2-Bute 3-Cl H 7 H                                                   Et H 3-Me-2-Bute 4-Cl H 7 H                                                   Et H Benz 3-Me H 7 3-NO.sub.2                                                 Et H Benz 2,3-diMeO H 7 H                                                     t-Bu H Me H 8-NO.sub.2 7 H                                                    Benz H 3-Me-2-Bute 4-MeO 8-Cl 7 H                                             Et H Benz H 9-MeO 7 H                                                         Et H 3-Me-2-Bute H 9-(3-Me--) 7 H                                             2-(diEtAm)Et H H H H 7 H                                                      3-(diMeAm)Pr H H H H 7 H                                                      3-(diMeAm)Pr H 3-Me-2-Bute H H 7 H                                            3-(1-Pipe)Pr H H H H 7 H                                                      3-(1-Pipe)Pr H Me H H 7 H                                                     3-(1-Mor)Pr H Benz H H 7 H                                                  __________________________________________________________________________     Remarks:                                                                      Me = methyl, Et = ethyl, Pr = propyl, iPr = isopropyl, ibutyl = isobutyl,     tbutyl = tertbutyl, benz = benzyl, 3Me-2-Bute = 3methyl-2-butenyl,            NO.sub.2 = nitro, MeO = methoxy, diMeO = dimethoxy, (diMeAm)Pr =              (dimethylamino)propyl, 2(1-Pyrro)Et = 2(1-pyrrolidinyl)ethyl, 9(3-Me--) =     9(3-methyl-2-butenyl), (diEtAm)Et = (diethylamino)ethyl  # (diEtAm)Pr =       (diethylamino)propyl 3(1-Pipe)Pr = 3(1-piperidinyl)propyl 3(1-Mor)Pr =        3(1-morpholinyl)propyl                                                   

Representative examples of the dihydrophenazinecarboxylic acidderivatives of the formula (I) (other than those shown in Tables 1 and2) are set forth in Tables 3 and 4.

                  TABLE 3                                                         ______________________________________                                        R.sup.1                                                                            R.sup.2   R.sup.3   R.sup.4  R.sup.5                                     ______________________________________                                        H    H         H         H        7-acetyl                                      Et H H H 7-acetyl                                                             Et H H H 7-Cl                                                                 Et H H H 7-trifluoromethyl                                                    Et H H H 7-(N-Mesulfamoyl)                                                    Et H H H 7-trifluoromethoxy                                                   H H 3-Me-2-Bute H 7-Cl                                                        Et H 3-Me-2-Bute H 7-Cl                                                       Et H 3-Me-2-Bute H 6-MeO                                                      Et Me 3-Me-2-Bute H 9-MeO                                                     Et H 3-Me-2-Bute H 7-trifluoromethyl                                          Et H 3-Me-2-Bute 3-Cl H                                                       Et H 3-Me-2-Bute 4-Cl H                                                       Et H 3-Me-2-Bute 4-Cl 7-Cl                                                    Et H 3-Me-2-Bute H 7,8-dichloro                                               i-Pr H 3-Me-2-Bute H 7-(N-Mesulfamoyl)                                        Et H Me H 8-methylsulfonyl                                                    Et H Me 2-Cl H                                                                Et H Me 3-Me H                                                                Et H Me 2,3-dimethoxy H                                                       t-Bu H Me H 7-trifluoromethoxy                                                t-Bu H Me H 7,8-dimethoxy                                                     Benz H Me H 7-cyano                                                           Et 3-Me-2-bute Me H 7-(N-Mesulfamoyl)                                         Benz H i-Bu 2,3-dimethoxy 7-trifluoro-                                            methyl                                                                  ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        R.sup.1  R.sup.2                                                                              R.sup.3     R.sup.4                                                                            R.sup.5                                      ______________________________________                                        Et       Me     Benz        H    8-dimethylamino                                Et H Benz H 8-(N-Mesulfamoyl)                                                 Et H 3-(diEtAm)Pr H 7-Cl                                                      Et H 2-(1-Pyrro)Et H 7,8-dimethoxy                                            2-(diEtAm)Et H H H 7-acetyl                                                   3-(diMeAm)Pr H H H 7-NO.sub.2                                                 3-(diMeAm)Pr H 3-Me-2-Bute H 7-Cl                                             3-(1-Pipe)Pr H Me H 8-methylsulfonyl                                          3-(1-Mor)Pr H Benz H 7-Br                                                   ______________________________________                                         Remarks:                                                                      8(N-Mesulfamoyl) = 8(N-methylsulfamoyl)                                  

Representative examples of the dihydrophenazinecarboxylic acidderivatives of the formula (V) (other than those shown in Tables 1 to 4)are set forth in Tables 5 and 6, in which the substituent group of --CO₂R⁴¹ is placed in the 2-position.

                  TABLE 5                                                         ______________________________________                                        R.sup.41                                                                             R.sup.42                                                                             R.sup.43    R.sup.44                                                                            R.sup.45                                      ______________________________________                                        H      H      H           H     7-benzoyl                                       H H H H 8-(N-Mesulfamoyl)                                                     H H H H 7-trifluoromethyl                                                     H H H H 7,8-dichloro                                                          H H 3-Me-2-Bute H 7-benzoyl                                                   Et H 3-Me-2-Bute H 7-benzoyl                                                  Et H 3-Me-2-Bute H 8-(N-Mesulfamoyl)                                          t-Bu Me 3-Me-2-Bute H 9-MeO                                                   t-Bu Me Me 4-MeO 7-benzoyl                                                  ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        R.sup.41  R.sup.42                                                                             R.sup.43   R.sup.44                                                                            R.sup.45                                    ______________________________________                                        Et        Benz   Benz       4-MeO 7,8-dichloro                                  Et H 3-(diEtAM)Pr H 7-trifluoromethyl                                         Et H 3-(1-Pipe)Pro H 8-methylsulfonyl                                         2-(diEtAm)Et H H H 7-benzoyl                                                  3-(diMeAm)Pr H H H 7-NO.sub.2                                                 3-(diMeAm)Pr H 3-Me-2-Bute H 7-benzoyl                                        3-(1-Pipe)Pr H Me H 9-NO.sub.2                                                3-(1-Mor)Pr H Benz H 7-benzoyl                                              ______________________________________                                    

The results of pharmacological tests are set forth below.

The dihydrophenazinecarboxylic acid derivatives of the formulas (I),(III) and (V) and their salts showed excellent cytoprotective action inthe glutamic acid toxicity inhibition tests using neurocyte (N18-RE-105cell) and first hippocampal cell (rat fetus origin) and the BSO toxicityinhibition tests using neurocyte (N18-RE-105 cell). See thebelow-mentioned Example 10.

The known compounds showing inhibition of glutamic acid toxicity wereeffective to inhibit death of neurocyte caused by light ischemia ofbrain and activate metabolism of brain. Accordingly, thedihydrophenazinecarboxylic acid derivatives of the formulas (I), (III),and (V) are also effective as therapeutic agents for cerebrovasculardiseases such as cerebral infarction and cerebrovacular dementia.

Further, the dihydrophenazinecarboxylic acid derivatives of the formulas(I), (III) and (V) and their salts showed excellent inhibition ofperoxidation of lipid in the tests for evaluation of peroxidationinhibitory action using rat whole brain homogenate, as is described bythe below-mentioned Example 10.

Examples of diseases assumed to be caused by active oxygen includeinflammation, articular rheumatism, and autoimmune disease. Therefore,the dihydrophenazinecarboxylic acid derivatives of the formulas (I),(III) and (V) are effective in treating these diseases.

The inhibitory agent for inhibition of the glutamic acid toxicitycontaining an effective amount of the dihydrophenazinecarboxylic acidderivatives of the formula (I), (III) and (V) can be administered in theform of an oral agent such as pellet, capsule and granule or aparantheral agent such as injection or depository. The inhibitory agentcan contain conventionally employed additives such as excipents such asglucose and lactose, disintegrators such as starch andcarboxymethylcellulose calcium (CMC-Ca), binders such ashydroxypropylcellulose (HPC) and polyvinyl pyrrolidone (PVP), lubricantssuch as talc and magnesium stearate, diluents, and dyes.

The dihydrophenazinecarboxylic acid derivative of the formula (I), (III)or (V) can be administered into an adult at the dosage of approximately0.001 mg to 100 mg/day in the case of injection and at the dosage ofapproximately 0.01 mg to 1.0 g/day in the case of oral administration.The dosage can be varied depending upon age, conditions, and others ofthe patient.

The present invention is further described by the following examples.

REFERENCE EXAMPLE 1

(1) N-(4-Benzoyl-2-nitrophenyl)anthranilic acid

A mixture of anthranilic acid (1.37 g, 10 mmol.),4-chloro-3-nitrobenzophenone (2.88 g, 11 mmol.), anhydrous potassiumcarbonate (powder, 2.77 g, 20 mmol.), copper (powder, 50 mg), andisoamyl alcohol (25 mL) was stirred and heated for one hour underreflux. The reaction mixture was cooled to room temperature, and stirredfor 15 minutes after addition of water (30 mL) and ether (30 mL). Theinsoluble red-brown solid was collected by filtration and washed withwater and ether. The red-brown solid mainly comprising a potassium saltof the desired compound was suspended in water (40 mL). To thesuspension was added 2M hydrochloric acid until an aqueous portion ofthe suspension showed approximately pH 2. The suspension was vigorouslystirred for one hour at room temperature. The deposited crystallineprecipitate was collected by filtration and washed with several portionsof water and ether. The washed precipitate was placed under reducedpressure at 60° C. for 3 hours to dryness. Thus, 2.34 g (65%) of thedesired compound was obtained as a yellow-orange crystalline product.

¹ H NMR (CD₃ OD/CDCl₃ =1/1) δ: 7.25 (1H, br), 7.53-7.80 (8H, m), 7.97(1H, brd, J=8Hz), 8.12 (1H, br), 8.68 (1H, d, J=2Hz).

(2) N-acetyl-N-(4-benzoyl-2-nitrophenyl)anthranilic acid

The above-obtained compound (8.70 g, 24.0 mmol.) was suspended inpyridine (100 mL). The suspension was stirred at room temperature forone day after addition of acetic anhydride (12.3 g, 0.12 mol.). Thesuspension was placed under reduced pressure to distill the solvent off.Water was added to the residue. The resulting aqueous suspension wasmade acidic by 2M hydrochloric acid until the aqueous portion reachedapproximately pH 2. The deposited precipitate was stirred at roomtemperature to turn it to powder. The crystalline powder was collectedby filtration and washed with water. The washed powder was placed underreduced pressure at 60° C. for 5 hours to dryness. Thus, 9.50 g (98%) ofthe desired compound was obtained as a pale yellow powder.

¹ H NMR (CD₃ OD/CDCl₃ =2/1) δ: 1.98 (3H, s), 7.30 (1H, d, J=8Hz),7.51-7.84 (8H, m), 7.94 (1H, dd, J=8, 2Hz), 8.23 (1H, dd, J=8, 1Hz),8.33 (1H, d, J=2Hz).

(3) ethyl N-acetyl-N-(4-benzoyl-2-nitrophenyl)anthranilate

In gaseous nitrogen atmosphere, the above-obtained compound (10.1 g,25.0 mmol.) was suspended in anhydrous methylene chloride (80 mL). Tothe suspension were added 4-dimethylaminopyridine (3.36 g, 27.5 mmol.)and anhydrous ethanol (1.82 mL, 31.2 mmol.). The resulting mixture waschilled with ice, and stirred at 5° C. for one hour and at roomtemperature for 16 hours, after addition of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g,27.5 mol.). The reaction mixture was placed under reduced pressure todistill the solvent off. The residue was mixed with water and ethylacetate, and the organic portion was taken out. The organic portion wasthen washed successively with 1M hydrochloric acid, saturated aqueoussodium hydrogencarbonate solution, and saturated aqueous sodium chloridesolution. The washed organic portion was dried over anhydrous sodiumsulfate and placed under reduced pressure to distill the solvent off.The residue was recrystallized from ethanol (180 mL) to give 8.88 g(82%) of the desired compound. Further, 0.31 g (3%) of a secondarycrystalline product was obtained from the mother liqueur.

¹ H NMR (CDCl₃) δ: 1.32 (3H, t, J=7Hz), 1.96 (3H, s), 4.40 (2H, q,J=7Hz), 7.18 (1H, d, J=8Hz), 7.48-7.58 (3H, m), 7.60-7.68 (3H, m),7.77-7.82 (2H, m), 7.92 (1H, dd, J=8, 2Hz), 8.14 (1H, br d, J=8Hz), 8.32(1H, d, J=2Hz). FAB-MS m/z 433 (MH⁺)

(4) 7-benzoyl-1-ethoxycarbonylphenazine 5-oxide

The above-obtained compound (8.75 g, 20.2 mmol.) was dissolved inacetonitrile (2.0 L). In gaseous nitrogen atmosphere, to the solutionwas irradiated for 10 hours a light from a 400W high pressure mercurylamp through a Pyrex filter. The reaction mixture was placed underreduced pressure to distill the solvent off. The residue was purified bymedium pressure column chromatography (chloroform,chloroform/methanol=100/1). The resulting product was dissolved inheated ethanol (20 mL). The solution was allowed to stand overnight atroom temperature. The deposited crystalline product was collected byfiltration and washed with ethanol and ether. The washed product wasplaced under reduced pressure to dryness, to give 4.18 g (55%) of thedesired compound as a yellow crystalline product. mp: 136-139° C.

¹ H NMR (CDCl₃) δ: 1.52 (3H, t, J=7Hz), 4.60 (2H, q, J=7Hz), 7.53-7.58(2H, m), 7.68 (1H, m), 7.79 (1H, dd, J=9, 7Hz), 7.88-7.92 (2H, m), 8.19(1H, dd, J=7, 1Hz), 8.31 (1H, dd, J=9, 2Hz), 8.38 (1H, d, J=9Hz), 8.80(1H, dd, J=9, 1Hz), 8.99 (1H, d, J=1Hz). FAB-MS m/z 373 (MH⁺) IR (KBr)νcm⁻¹ : 1720, 1650, 1430, 1350, 1295, 1280, 1190, 1135, 725.

EXAMPLE 1

Ethyl 7-benzoyl-5,10-dihydro-1-phenazinecarboxylate

To a boiled ethanol solution (300 mL) of7-benzoyl-1-ethoxycarbonylphenazine 5-oxide (4.00 g, 10.7 mmol. obtainedin Reference Example 1) was dropwise added for a period of one hour anaqueous solution (150 mL) of 85% sodium hydrosulfate (8.86 g, 43.2 mol.)in gaseous nitrogen atmosphere. After the dropwise addition wascomplete, the reaction mixture was further heated under reflux for 10minutes. The refluxed mixture was then cooled to room temperature. Tothe cooled mixture was added water (150 mL). Thus deposited crystallineproduct was collected by filtration and washed with water. The washedproduct was placed under reduced pressure at 40° C. for 16 hours in thepresence of diphosphorus pentoxide to dryness. Thus, 3.10 g (81%) of thedesired compound was obtained as a brown-violet crystalline product. mp:175-177° C.

¹ H NMR (CD₃ OD/CDCl₃ =1/1) δ: 1.37 (3H, t, J=7Hz), 4.29 (2H, q, J=7Hz),6.10 (1H, d, J=8Hz), 6.12 (1H, dd, J=8, 1Hz), 6.34 (1H, dd, J=8, 8Hz),6.54 (1H, d, J=2Hz), 6.83 (1H, dd, J=8, 2Hz), 6.95 (1H, dd, J=8, 1Hz),7.43-7.49 (2H, m), 7.56 (1H, m), 7.64-7.68 (2H, m), 8.97 (1H, br s). IR(KBr) νm⁻¹ : 3310, 1655, 1630, 1605, 1590, 1560, 1470, 1440, 1315, 1290,1250, 1220, 1155, 1120, 1075, 1000, 740, 705.

EXAMPLE 2

Ethyl7-benzoyl-5,10-dihydro-5-(3-methyl-2-butenyl)-1-phenazinecarboxylate

In a 2-butanone suspension (6 mL) of the compound (359 mg, 1.00 mmol.)obtained in Example 1 were placed anhydrous potassium carbonate (powder,0.83 g, 6.0 mmol.) and 4-bromo-2-methyl-2-butene (0.44 g, 3.0 mmol). Theresulting mixture was refluxed for 7 hours with vigorous stirring ingaseous nitrogen atmosphere. The reaction mixture was cooled to roomtemperature, and then mixed with water and ethyl acetate. The organicportion was taken out. The aqueous portion was extracted with ethylacetate. The organic portions were combined and washed with saturatedaqueous sodium chloride solution. The washed organic portion was driedover anhydrous sodium sulfate and placed under reduced pressure todistill the solvent off. The residue was treated by medium pressurecolumn chromatography (chloroform/hexane=2/1) to give a crude product(337 mg). The crude product was recrystallized from hexane containing asmall amount of ethyl acetate to give 221 mg (52%) of the desiredcompound as a needle crystalline product. mp: 107-108° C.

¹ H NMR (CDCl₃) δ: 1.36 (3H, t, J=7Hz), 1.70 (3H, br s), 1.74 (3H, brs), 3.97 (2H, br d, J=5Hz), 4.30 (2H, q, J=7Hz), 5.06 (1H, m), 6.17 (1H,d, J=8Hz), 6.19 (1H, br d, J=8Hz), 6.46 (1H, dd, J=8, 8Hz), 6.72 (1H, brs), 6.96 (1H, dd, J=8, 2Hz), 7.08 (1H, dd, J=8, 1Hz), 7.40-7.46 (2H, m),7.52 (1H, m), 7.67-7.71 (2H, m), 9.45 (1H, br s). FAB-MS m/z 426 (M⁺) IR(KBr) νcm⁻¹ : 3250, 1675, 1640, 1585, 1500, 1470, 1445, 1270, 1250,1240, 1135, 735.

EXAMPLE 3

Ethyl7-benzoyl-5,10-dihydro-5,10-bis(3-methyl-2-butenyl)-1-phenazinecarboxylate

Anhydrous THF solution (1 mL) of the compound (43 mg, 0.10 mmol.)obtained in Example 2 was chilled with ice. To the chilled solution wereadded successively 60% sodium hydride (6 mg, 0.15 mmol.) and after 5minutes 4-bromo-2-methyl-2-butene (18 μL, 0.15 mmol.) in gaseousnitrogen atmosphere. The reaction mixture was stirred at 5° C. for onehour and at room temperature for 40 minutes. The reaction mixture wasmixed with 10% aqueous citric acid solution (1 mL) and water (10 mL).The resulting mixture was extracted with ethyl acetate. The extract waswashed with saturated aqueous sodium hydrogen-carbonate solution andsaturated aqueous sodium chloride solution, and dried over anhydroussodium sulfate. The dried solution was placed under reduced pressure todistill the solvent off. The residue was purified by preparative thinlayer chromatography (ethyl acetate/hexane=1/3) to give 50 mg (100%) ofthe desired compound as red oil.

¹ H NMR (CDCl₃) δ: 1.38 (3H, t, J=7Hz), 1.63 (3H, d, J=1Hz), 1.64 (3H,br s), 1.69 (3H, br s), 1.72 (3H, d, J=1Hz), 4.05 (2H, br d, J=6Hz),4.20 (2H, br d, J=5Hz), 4.33 (2H, q, J=7Hz), 5.09-5.19 (2H, m), 6.41(1H, d, J=8Hz), 6.48 (1H, dd, J=8, 1Hz), 6.74 (1H, dd, J=8, 8Hz), 6.91(1H, d, J=2Hz), 7.08 (1H, dd, J=8, 1Hz), 7.18 (1H, dd, J=8, 2Hz),7.41-7.47 (2H, m), 7.53 (1H, m), 7.70-7.75 (2H, m).

EXAMPLE 4

Ethyl 7-benzoyl-5-benzyl-5,10-dihydro-1-phenazinecarboxylate

To 2-butanone solution (4 mL) of the compound (180 mg, 0.502 mmol.)obtained in Example 1 were added anhydrous potassium carbonate (powder,415 mg, 3.0 mmol.) and benzyl bromide (257 mg, 1.5 mmol.). The mixturewas refluxed for 10 hours under vigorous stirring in gaseous nitrogenatmosphere. The reaction mixture was cooled to room temperature andmixed with water and ethyl acetate. The organic portion was taken out.The aqueous portion was extracted with ethyl acetate. The organicportions were combined, washed with saturated aqueous sodium chloridesolution, and dried over anhydrous sodium sulfate. The dried organicportion was placed under reduced pressure to distill the solvent off.The residue was purified by medium pressure column chromatography(chloroform/hexane=2/1), to give 141 mg (63%) of the desired compound asan orange crystalline product. mp: 134-136° C.

¹ H NMR (CDCl₃) δ: 1.37 (3H, t, J=7Hz), 4.31 (2H, q, J=7Hz), 4.62 (2H,br s), 6.08 (1H, br d, J=8Hz), 6.22 (1H, d, J=8Hz), 6.35 (1H, dd, J=8,8Hz), 6.62 (1H, br s), 6.99 (1H, dd, J=8, 2Hz), 7.09 (1H, dd, J=8, 1Hz),7.25-7.38 (7H, m), 7.45 (1H, m), 7.56-7.61 (2H, m), 9.53 (1H, br, s). IR(KBr) νcm⁻¹ : 3280, 1670, 1635, 1610, 1585, 1520, 1495, 1470, 1440,1315, 1270, 1250, 1140, 750, 705.

EXAMPLE 5

Ethyl 7-benzoyl-5,10-dihydro-5-methyl-1-phenazinecarboxylate

To an acetone suspension (4 mL) of the compound (180 mg, 0.502 mmol.)obtained in Example 1 were added anhydrous potassium carbonate (powder,415 mg, 3.0 mmol.) and methyl iodide (0.19 mL, 3.0 mmol.). The mixturewas heated under reflux with vigorous stirring in gaseous nitrogenatmosphere. After 4 hours, methyl iodide (0.19 mL, 3.0 mmol.) was againadded to the reaction mixture. The reaction mixture was refluxed furtherfor 16 hours. The reaction mixture was cooled to room temperature andmixed with water and ethyl acetate. The organic portion was taken out.The aqueous portion was extracted with ethyl acetate. The organicportions were combined, washed with saturated aqueous sodium chloridesolution, and dried over anhydrous sodium sulfate. The dried organicportion was placed under reduced pressure to distill the solvent off.The residue was purified by medium pressure column chromatography(chloroform/hexane=2/1), to give 50 mg (27%) of the desired compound asan orange crystalline product. mp; 139-141° C.

¹ H NMR (CDCl₃) δ: 1.37 (3H, t, J=7Hz), 2.94 (3H, s), 4.31 (2H, q,J=7Hz), 6.20 (1H, d, J=8Hz), 6.28 (1H, br d, J=8Hz), 6.53 (1H, dd, J=8,8Hz), 6.85 (1H, br s), 6.96 (1H, dd, J=8, 2Hz), 7.13 (1H, dd, J=8, 1Hz),7.42-7.47 (2H, m), 7.53 (1H, m), 7.68-7.72 (2H, m), 9.49 (1H, br s). IR(KBr) νcm⁻¹ : 3260, 1680, 1640, 1590, 1550, 1500, 1475, 1440, 1420,1320, 1275, 1250, 1240, 1170, 1140, 750, 740, 710.

EXAMPLE 6

3-(Dimethylamino)-propyl 7-benzoyl-5,10-dihydro-1-phenazinecarboxylate

(1) ethyl 7-benzoyl-1-phenazinecarboxylate

To a methanol suspension (6 mL) of 7-benzoyl-1-ethoxycarbonylphenazine5-oxide (56 mg, 0.15 mmol.) obtained in Reference Example 1 was dropwiseadded an aqueous solution (2 mL) of sodium hydrosulfite (85%, 131 mg,0.64 mmol.). The mixture was stirred for one hour at room temperature,and extracted with ethyl acetate after addition of water. The extractwas washed with water and saturated aqueous sodium chloride solution,and dried over anhydrous sodium sulfate. The dried solution was placedunder reduced pressure to distill the solvent off. The residue waspurified by preparative thin layer chromatography (ethylacetate/hexane=1/1), to give the desired compound as a yellowcrystalline product. mp: 115-116° C.

¹ H NMR (CDCl₃) δ: 1.53 (3H, t, J=7Hz), 4.62 (2H, q, J=7Hz), 7.53-7.59(2H, m), 7.67 (1H, m), 7.89 (1H, dd, J=9, 7Hz), 7.91-7.96 (2H, m), 8.27(1H, dd, J=7, 1Hz), 8.34 (1H, dd, J=9, 2Hz), 8.37 (1H, dd, J=9, 1Hz),8.44 (1H, d, J=9Hz), 8.60 (1H, d, J=2Hz).

(2) 7-benzoyl-1-phenazinecarboxylic acid

To an ethanolic suspension (0.8 mL) of ethyl7-benzoyl-1-phenazinecarboxylate (36 mg, 0.10 mmol.) obtained above wasadded 1M aqueous sodium hydroxide solution (0.20 mL, 0.20 mmol.). Themixture was then stirred for 4 hours at room temperature. The reactionmixture was further stirred for 0.5 hour after addition water (2 mL) and0.5M hydrochloric acid (1 mL). The deposited crystalline product wascollected by filtration and washed with water. The washed product wasplaced under reduced pressure at 40° C. for 16 hours, to give 33 mg(100%) of the desired compound as a yellow crystalline product. mp:236-237° C.

¹ H NMR (CDCl₃) δ: 7.55-7.62 (2H, m), 7.70 (1H, m), 7.92-7.97 (2H, m),8.09 (1H, dd, J=9, 7Hz), 8.42 (1H, d, J=9Hz), 8.48 (1H, dd, J=9, 1Hz),8.55 (1H, dd, J=9, 1Hz), 8.70 (1H, d, J=1Hz), 9.06 (1H, dd, J=7, 1Hz).IR (KBr) νcm⁻¹ : 3050, 1740, 1650, 1590, 1405, 1315, 1285, 1240, 1170,855, 760, 735, 720, 705.

(3) 3-(dimethylamino)propyl 7-benzoyl-1-phenazinecarboxylate

In an anhydrous dichloromethane suspension (3 mL) of7-benzoyl-1-phenazinecarboxylic acid (66 mg, 0.20 mmol.) obtained abovewere added 4-dimethylaminopyridine (27 mg, 0.22 mmol.) and3-dimethylamino-1-propanol (28 μL, 0.24 mmol.). The mixture was chilledwith ice. To the mixture was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (43 mg, 0.22mmol.). The resulting mixture was stirred at 5° C. for one hour and atroom temperature for 21 hours. The reaction mixture was concentrated,and the residue was diluted with ethyl acetate and 5% aqueous sodiumhydrogencarbonate solution. The organic portion was taken out, washedwith water and saturated aqueous sodium chloride solution, and driedover anhydrous sodium sulfate. The dried mixture was placed underreduced pressure to distill the solvent off. The residue was purified bypreparative thin layer chromatography (chloroform/methanol=5/1), to give73 mg (88%) of the desired compound as a pale yellow solid product.

¹ H NMR (CDCl₃) δ: 2.10 (2H, m), 2.34 (6H, s), 2.63 (2H, br t, J=7Hz),4.61 (2H, t, J=6Hz), 7.54-7.59 (2H, m), 7.67 (1H, m), 7.90 (1H, dd, J=9,7Hz), 7.90-7.96 (2H, m), 8.28 (1H, dd, J=7, 1Hz), 8.35 (1H, dd, J=9,2Hz), 8.38 (1H, dd, J=9, 1Hz), 8.44 (1H, d, J=9Hz), 8.60 (1H, d, J=2Hz).

(4) 3-(dimethylamino)propyl7-benzoyl-5,10-dihydro-1-phenazinecarboxylate

The procedures of Example 1 were repeated using 3-(dimethylamino)propyl7-benzoyl-1-phenazinecarboxylate (406 mg, 0.601 mmol) obtained above, togive the desired compound (350 mg, 86%).

¹ H NMR (CDCl₃) δ: 1.90 (2H, m), 2.25 (6H, s), 2.41 (2H, t, J=7Hz), 4.29(2H, t, J=7Hz), 5.14 (1H, s), 6.09 (1H, bd, J=7Hz), 6.12 (1H, d, J=8Hz),6.36 (1H, dd, J=8, 7Hz), 6.61 (1H, d, J=1Hz), 6.90 (1H, dd, J=8, 2Hz),7.01 (1H, dd, J=8, 1Hz), 7.42-7.69 (5H, m), 9.04 (s, 1H).

EXAMPLE 7

3-(1-Piperidinyl)-propyl 7-benzoyl-5,10-dihydro-1-phenazinecarboxylate

(1) 3-(1-piperidinyl)propyl 7-benzoyl-1-phenazine carboxylate

The procedures of Example 6(3) were repeated using7-benzoyl-1-phenazinecarboxylic acid (700 mg, 2.13 mmol.) obtained inExample 6(2) and 3-(1-piperidinyl)-1-propanol (366 mg, 2.56 mmol.), togive the desired compound (665 mg, 69%).

¹ H NMR (CDCl₃) δ: 1.43-1.63 (6H, m), 2.10 (2H, m), 2.46 (4H, bs), 2.61(2H, t, J=7Hz), 4.60 (2H, t, J=7Hz), 7.54-7.69 (3H, m), 7.89 (1H, dd,J=9, 7Hz), 7.92-7.95 (2H, m), 8.27 (1H, dd, J=7, 1Hz), 8.35 (1H, dd,J=9, 2Hz), 8.38 (1H, dd, J=9, 1Hz), 8.44 (1H, d, J=9Hz), 8.60 (1H, d,J=2Hz).

(2) 3-(1-piperidinyl)propyl7-benzoyl-5,10-dihydro-1-phenazinecarboxylate

The procedures of Example 1 were repeated using 3-(1-piperidinyl)propyl7-benzoyl-1-phenazinecarboxylate (600 mg, 1.32 mmol.) obtained above, togive the desired compound (370 mg, 61%).

¹ H NMR (CDCl₃) δ: 1.42-2.02 (10H, m), 2.10 (2H, m), 2.55 (4H, bs), 4.27(2H, t, J=6Hz), 5.06 (1H, s), 6.07 (1H, bd, J=7Hz), 6.11 (1H, d, J=8Hz),6.35 (1H, t, J=8Hz), 6.60 (1H, d, J=2Hz), 6.90 (1H, dd, J=2, 8Hz), 6.99(1H, bd, J=8Hz), 7.41-7.69 (5H, m), 9.00 (1H, s).

EXAMPLE 8

3-(Dimethylamino)-propyl7-benzoyl-5,10-dihydro-5-(3-methyl-2-butenyl)-1-phenazinecarboxylate

In toluene (12 mL) was dissolved ethyl7-benzoyl-5,10-dihydro-5-(3-methyl-2-butenyl)-1-phenazinecarboxylate(1.26 g, 2.95 mmol.) obtained in Example 2. To the mixture were furtheradded 3-(dimethylamino)-1-propanol (3.50 mL, 29.5 mmol.) andtetra-n-butyl-1-isothiocyanate-3-hydroxydistannoxane (SCN(n-Bu)₂SnOSn(n-Bu)₂ OH; 329 mg, 0.591 mmol.). The mixture was stirred at 100°C. for 24 hours in the stream of gaseous nitrogen. The mixture wasfurther stirred at 100° C. for 24 hours, after addition of3-(dimethylamino)-1-propanol (1.50 mL) and the above-mentioned tincompound (329 mg, 0.591 mmol.). The reaction mixture was cooled to roomtemperature and poured into saturated aqueous sodium hydrogencarbonatesolution. The aqueous mixture was then extracted with ethyl acetate. Theextract was washed with two portions of saturated aqueous sodiumchloride solution and dried over anhydrous sodium sulfate. The driedextract was placed under reduced pressure to distill the solvent off.The residue was purified by medium pressure column chromatography (CHCl₃/methanol=1/0→95/5), to give the desired compound (142 mg, 10%).

¹ H NMR (CDCl₃) δ: 1.70 (3H, bs), 1.75 (3H, bs), 1.91 (2H, m), 2.25 (6H,s), 2.41 (2H, t, J=7Hz), 3.97 (2H, bd, J=5Hz), 4.30 (2H, t, J=6Hz), 5.06(1H, m), 6.17 (1H, d, J=8Hz), 6.19 (1H, bd, J=9Hz), 6.46 (1H, t, J=8Hz),6.72 (1H, d, J=1Hz), 6.97 (1H, dd, J=1, 8Hz), 7.06 (1H, dd, J=1, 8Hz),7.42-7.70 (5H, m), 9.44 (1H, s).

EXAMPLE 9

3-(Dimethylamino)propyl7-benzoyl-5,10-dihydro-5-(3-methyl-2-butenyl)-1-phenazinecarboxylatehydrochloride

To an ethanolic solution (2 mL) of 3-(dimethylamino)propyl7-benzoyl-5,10-dihydro-5-(3-methyl-2-butenyl)-1-phenazinecarboxylate(135 mg, 0.279 mmol.) obtained in Example 8 was added hydrogenchloride/ether (1M solution, 0.42 mL). The mixture was stirred at roomtemperature for one hour. The reaction solution was placed under reducedpressure to concentrate it to dryness, to give the desired compound (135mg, 93%) as a red-violet amorphous product.

¹ H NMR (DMSO-₆) δ: 1.62 (3H, bs), 1.71 (3H, bs), 2.10 (2H, m), 2.78(3H, s), 2.80 (3H, s), 3.18 (2H, m), 3.98 (2H, bd, J=5Hz), 4.29 (2H, t,J=6Hz), 5.00 (1H, m), 6.34 (1H, bd, J=8Hz), 6.50-6.58 (3H, m), 6.92 (1H,bd, J=8Hz), 7.06 (1H, bd, J=8Hz), 7.49-7.62 (5H, m), 9.27 (1H, s), 10.0(1H, bs).

REFERENCE EXAMPLE 2

Ethyl 7-benzoyl-5,10-dihydro-5-methoxycarbonyl-1-phenazinecarboxylate

To an anhydrous THF solution (10 mL) of the compound (359 mg, 1.00mmol.) obtained in Example 1 were successively added 60% sodium hydride(40 mg, 1.00 mmol.) and after 5 minutes ethyl chlorocarbonate (120 μL,1.57 mmol.) under chilling with ice and in gaseous nitrogen atmosphere.The mixture was stirred at 5° C. for one hour and at room temperaturefor 20 hours. The reaction mixture was mixed with 1M hydrochloric acid(1 mL) and water (40 mL) and then extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium chloride solution anddried over anhydrous sodium sulfate. The dried extract was placed underreduced pressure to distill the solvent off. The residue was purified bymedium pressure column chromatography (chloroform), to give 166 mg (40%)of the desired compound as a yellow crystalline product. mp: 112-115° C.

¹ H NMR (CDCl₃) δ: 1.42 (3H, t, J=7Hz), 3.82 (3H, s), 4.39 (2H, q), 6.87(1H, d), 6.96 (1H, dd, J=8, 8Hz), 7.46-7.60 (2H, m), 7.52-7.60 (2H, m),7.66 (1H, dd, J=8, 2Hz), 7.77-7.82 (3H, m), 7.86 (1H, d, J=2Hz), 9.94(1H, br s).

EXAMPLE 10

(1) Test for inhibition of glutamic acid toxicity to neurocyte

The test was carried out using hybridoma (N18-RE-105 cell) of mouseneuroblastoma and rat retinal neurocyte.

Neuron 2, 1547 (1989) and J. Pharmacol. Exp. Ther, 250, 1132 (1989)report that death of cell is caused owing to oxidative stressoriginating from disturbance of cystine uptake into cells when a highconcentration of glutamic acid (1-10 mM) is added to hybridoma.

The dihydrophenazinecarboxylic acid derivatives of the invention wereexamined in the action to the glutamic acid-induced cell death. Ascontrol, ethyl7-benzoyl-5,10-dihydro-5-methoxycarbonyl-1-phenazinecarboxylate having astructure analogous to the compound of the invention, and the knownantioxidants (nicaraven and ebselen) were examined.

Hybridoma cells were plated at 6.25×10³ cells/cm². on on 96 wellmicroplate in Dalbecco's modified MEM containing 10% FBS (fetal bovineserum) and HAT (hypoxanthine 0.1 mM, aminopterin 40 nM, thymidine 0.14mM, Sigma Chem., Co.). After 24 hours, 10 mM glutamic acid and the testcompound were added to the culture medium. After the addition ofglutamic acid, the culture was maintained for further 24 hours. Then,the activity of lactate dehydrogenase (LDH) contained in the cells andthe medium was determined. The LDH releasing ratio was calculated usingthe below-mentioned equation to examine the glutamic acid toxicity.

LDH releasing ratio=[LDH activity in medium/(LDH activity in cells andLDH activity in medium)]×100

(2) Test for inhibition of BSO toxicity to neurocyte (neurocyteprotective action against cytotoxicity accompanied by decrease of amountof intracellular glutathione)

Neuron 2, 1547 (1989) and Experimental Medicine, 11, 2412 (1993) suggestthat cause of the cell death of neurocyte N18-RE-105 is explained by thefact that the uptake of cystine by way of cystine/glutamic acidexchanging system is disturbed to deplete intracellular glutathione,whereby the oxidative stress does not diminish.

In view of the above-mentioned suggestion, the cytotoxicity ofD,L-butionine (S,R)-sulfoximine (BSO), which is a glutathione-synthaseinhibitor, was studied.

The culture of neurocyte N18-RE-105, addition of the test compound, anddetermination of lactate dehydrogenase (LDH) were carried out in themanner as described in (1) above. BSO was added at the concentration of500 μM.

(3) Test for inhibition of glutamic acid toxicity to hippocampal cellsin primary culture

1) Preparation of hippocampal cells (from rat fetus in primary culture)

A pregnant rat (18 days pregnancy) was anesthetized by Pentobarbitalsodium. Its abdomen was sterilized using 83% ethanol and treated to takeits fetus out. The whole brain was taken out from the fetus understereomicroscopical observation. From the brain, its hippocampal portionwas taken out. The hippocampal portion was cut into small pieces using aknife. The procedures for taking the hippocampal portion out and cuttingthe portion into small pieces were performed in a Hanks buffer solution(4° C.) without Ca²⁺ and Mg²⁺. The pieces of hippocampus were treatedwith 0.25% trypsin/0.01% DNase I solution at 37° C. for 30 minutes.After the addition of dialyzed FBS at the concentration of 20%, thetreated specimen was recovered by centrifugal separation and suspendedin DMEM containing GMS-A obtained from GIBCO (S1 culture medium). Thespecimen was gently treated by a pipet to give a cell suspension. Thecells were plated at 1.0×10⁵ cells/cm² on 48-well multiplate pre-coatedwith poly-L-lysine. After 3 hours, dialyzed FBS was added to give afinal concentration of 10%. The cells were cultured at 37° C. for 4 daysin 5% CO₂ atmosphere.

2) Determination of activity (Lactate dehydrogenase (LDH) method)

The cytoprotective action of the test compound was determined bymeasuring activity of LDH released from the dead cells and activity ofLDH in the living cells. The hippocampal cells were cultured for 4 days,and then cultured for 48 hours in S1 culture medium (FBS was not added)containing 1 mM glutamic acid and the test compound. After the culturingprocedure was complete, the activity of lactate dehydrogenase wasdetermined in the manner described in 1) above.

(4) Test for inhibition of production of peroxidized lipid in rat wholebrain homogenate

From the rat which had been fed with vitamin E deficient food for 11weeks, a whole brain was taken out and frozen in liquid nitrogen. Afterthe frozen whole brain was pulverized to give a powder, it washomogenized by Dounce type homogenizer. The homogenate was subjected tocentrifugal separation at 180×g for 10 minuets, and the supernatant wasrecovered. The recovered supernatant was employed as the whole brainhomogenate. The reaction of lipid peroxidation was initiated bystimulation using iron-ascorbic acid. The peroxidized lipid wasquantitatively analyzed by the thiobarbituric acid (TBA) method. In moredetail, 200 μL of the whole brain homogenate (protein content: 12.5mg/mL), 50 μL of ADP (2 mg/mL), 50 μL of FeSO₄ (0.5 mM), 50 μL ofascorbic acid (12 mM), and 50 μL of the test compound were added to 100μL of 0.2M Tris-HCl buffer solution. The mixture was incubated at 37° C.for one hour. After the incubation was complete, 50 μL of 0.5%butylhydroxytoluene/ethanol solution, 250 μL of 8.1% SDS (sodiumdodecylsulfate) solution, 1,750 μL of 20% acetic acid, and 1,500 μL of0.8% TBA solution were added to the incubated mixture. The resultingmixture was boiled for one hour. After the boiling was complete, themixture was cooled and then subjected to centrifugal separation at1,500×g for 10 minutes. The separated supernatant was subjected tomeasurement of absorbance at 535 nm.

The results of the above-mentioned pharmacological tests (1), (2), (3)and (4) are set forth in Table 7.

                  TABLE 7                                                         ______________________________________                                                            Hippo-                                                      N18-RE-105 campal Rat whole brain                                             Cell cell homogenate                                                        Test    Glutamic  BSO       Glutamic                                                                             (Inhibition of                               compound EC.sub.50 (nM) EC.sub.50 (nM) EC.sub.25 (nM) lipid peroxid)        ______________________________________                                        Compound 1                                                                            3.3       6         --     --                                           Compound 2 14.5 96.2 12   60.2                                                Compound 3 40.7 72 -- --                                                      Compound 4 58 90 -- --                                                        Compound 5 --  --  57.5 --                                                    Comparative >1,000 >1,000 -- --                                               Nicarven >100 × 10.sup.3 >100 × 10.sup.3 -- --                    Ebselen  10.1 × 10.sup.3   7.5 × 10.sup.3 -- --                 ______________________________________                                         Remarks:                                                                      In Table 7, "Glutamic" and "BSO" mean "Glutamic acid toxicity" and "BSO       toxicity", respectively. "Inhibition of lipid peroxid" means "Inhibition      of lipid peroxidation" and the number means "% per control value              (10.sup.-4 M)".                                                               Compound 1: ethyl 7benzoyl-5,10-dihydro-1-phenazinecarboxylate                Compound 2: ethyl                                                             7benzoyl-5,10-dihydro-5-(3-methyl-2-butenyl)-1-phenazinecarboxylate           Compound 3: ethyl 7benzoyl-5-benzyl-5,10-dihydro-1-phenazinecarboxylate       Compound 4: ethyl 7benzoyl-5,10-dihydro-5-methyl-1-phenazinecarboxylate       Compound 5: 3(dimethylamino)propyl                                            7benzoyl-5,10-dihydro-5-(3-methyl-2-butenyl)-1-phenazinecarboxylate           hydrochloride                                                                 Comparative: ethyl                                                            7benzoyl-5,10-dihydro-5-methoxy-carbanyl-1-phenazinecarboxylate          

From the results of Table 7, it is confirmed that the compounds of theinvention have excellent cytoprotective activity to inhibit glutamicacid toxicity in neurocyte (N18-RE-105 cell) and hippocampal cell fromrat fetus in primary culture. It is further confirmed that the compoundhave excellent cytoprotective activity to BSO toxicity in the neurocyte(N18-RE-105 cell).

In contrast, the comparative compound and the known antioxidants such asnicarven and ebseen showed no cytoprotective action to the glutamic acidtoxicity and BSD toxicity in the neurocyte.

Moreover, it is confirmed from the results of Table 7 that the compoundsof the invention show excellent inhibition of lipid peroxidation in thetest for evaluating inhibition of lipid peroxidation using rat wholebrain homogenate.

EXAMPLE 11

Acute toxicity

The compound of the invention (ethyl7-benzoyl-5,10-dihydro-1-phenazinecarboxylate obtained in Example 1) wasadministered to ddY strain male mice (weight: 23 to 27 g) in a dose of 5mg by intravenous injection. No death was observed.

What is claimed is:
 1. A dihydrophenazinecarboxylic acid derivativehaving the formula (I): in which ##STR15## in which R¹ represents ahydrogen atom, a linear or branched chain alkyl group, an aralkyl groupor an aryl group;each of R² and R³ is the same or different from eachother and represents a hydrogen atom, an alkenyl group having 2 to 5carbon atoms, an alkyl group, an aralkyl group, an aryl group, or agroup represented by the formula (II): ##STR16## wherein each of R⁶ andR⁷ is the same or different from each other and represents a hydrogenatom, a linear or branched chain alkyl group, an aralkyl group or anaryl group, or R⁶ and R⁷ are combined together to form a nitrogenatom-containing 5- to 7-membered ring in conjunction with the adjacentnitrogen atom, and m is 2, 3 or 4; each of R⁴ and R⁵ is the same ordifferent from each other and represents a hydrogen atom, a linear orbranched chain alkyl group, an alkenyl group, an alkynyl group, anaralkyl group, an aryl group, a hydroxyl group, an alkoxy group, anaryloxy group, an aralkyloxy group, a halogen atom, a nitro group, acyano group, an alkylsulfonyl group, an arylsulfonyl group, analkylcarbonyl group, an arylcarbonyl group, an aralkylcarbonyl group, ahalo-alkyl group, a halo-alkoxy group, or a group represented by --NR⁸R⁹ or --SO₂ NR¹⁰ R¹¹ wherein each of R⁸ and R⁹ is the same or differentfrom each other and represents a hydrogen atom, a linear or branchedchain alkyl group, an aralkyl group or an aryl group, and each R¹⁰ andR¹¹ is the same or different from each other and represents a hydrogenatom, a linear or branched chain alkyl group, an aralkyl group or anaryl group; provided that at least one of R⁴ and R⁵ is a group selectedfrom the group consisting of a nitro group, a cyano group, analkylsulfonyl group, an arylsulfonyl group, an alkylcarbonyl group, anarylcarbonyl group, an aralkylcarbonyl group, a trifluoromethyl group, atrifluoromethoxy group, and a group represented by --SO₂ NR¹⁰ R¹¹wherein each of R¹⁰ and R¹¹ is the same or different from each other andrepresents a hydrogen atom, a linear or branched chain alkyl group, anaralkyl group or an aryl group.
 2. A method for treating a patientsuffering from glutamic acid toxicity which comprises administering tothe patient an effective amount of a dihydrophenazinecarboxylic acidderivative of the following formula (V): ##STR17## in which R⁴¹represents a hydrogen atom, a linear or branched chain alkyl group, anaralkyl group or an aryl group;each of R⁴² and R⁴³ is the same ordifferent from each other and represents a hydrogen atom, an alkylgroup, an aralkyl group, an aryl group, an alkenyl group having 2 to 5carbon atoms, or a group represented by the formula (VI): ##STR18##wherein each of R⁴⁶ and R⁴⁷ is the same or different from each other andrepresents a hydrogen atom, a linear or branched chain alkyl group, anaralkyl group or an aryl group, or R⁴⁶ and R⁴⁷ are combined together toform a nitrogen atom-containing 5- to 7-membered ring in conjunctionwith the adjacent nitrogen atom, and p is 2, 3 or 4; each of R⁴⁴ and R⁴⁵is the same or different from each other and represents a hydrogen atom,a linear or branched chain alkyl group, an alkenyl group, an alkynylgroup, an aralkyl group, an aryl group, a hydroxyl group, an alkoxygroup, an aryloxy group, an aralkyloxy group, a halogen atom, a nitrogroup, a cyano group, an alkylsulfonyl group, an arylsulfonyl group, analkylcarbonyl group, an arylcarbonyl group, an aralkylcarbonyl group, ahalo-alkyl group, a halo-alkoxy group, a carboxyl group, analkoxycarbonyl group, an aralkyloxycarbonyl group, a formyl group, or agroup represented by --NR⁴⁸ R⁴⁹ or --SO₂ NR⁵⁰ R⁵¹ wherein each of R⁴⁸and R⁴⁹ is the same or different from each other and represents ahydrogen atom, a linear or branched chain alkyl group, an aralkyl groupor an aryl group, and each of R⁵⁰ and R⁵¹ is the same or different fromeach other and represents a hydrogen atom, a linear or branched chainalkyl group, an aralkyl group or an aryl group.
 3. The method of claim2, wherein at least one of R⁴⁴ and R⁴⁵ of the formula (V) is a groupselected from the group consisting of a nitro group, a cyano group, analkylsulfonyl group, an arylsulfonyl group, an alkylcarbonyl group, anarylcarbonyl group, an aralkylcarbonyl group, a trifluoromethyl group, atrifluoromethoxy group, and a group represented by --SO₂ NR⁵⁰ R⁵¹,wherein each of R⁵⁰ and R⁵¹ is the same or different from each other andrepresents a hydrogen atom, a linear or branched chain alkyl group, anaralkyl group or an aryl group.
 4. An inhibitory agent of glutamic acidtoxicity containing an effective amount of a dihydrophenazinecarboxylicacid derivative of the formula (I) set forth in claim
 1. 5. Adihydrophenazinecarboxylic acid derivative having the formula (III):##STR19## in which R²¹ represents a hydrogen atom, a linear or branchedchain alkyl group, an aralkyl group or an aryl group;each of R²² and R²³is the same or different from each other and represents a hydrogen atom,an alkenyl group having 2 to 5 carbon atoms, an alkyl group, an aralkylgroup, an aryl group, or a group represented by the formula (IV):##STR20## wherein each of R²⁶ and R²⁷ is the same or different from eachother and represents a hydrogen atom, a linear or branched chain alkylgroup, an aralkyl group or an aryl group, or R²⁶ and R²⁷ are combinedtogether to form a nitrogen atom-containing 5- to 7-membered ring inconjunction with the adjacent nitrogen atom, and n is 2, 3 or 4; each ofR²⁰, R²⁴ and R²⁵ is the same or different from each other and representsa hydrogen atom, a linear or branched chain alkyl group, an alkenylgroup, an alkynyl group, an aralkyl group, an aryl group, a hydroxylgroup, an alkoxy group, an aryloxy group, an aralkyloxy group, a halogenatom, a nitro group, a cyano group, an alkylsulfonyl group, anarylsulfonyl group, a halo-alkyl group, a halo-alkoxy group, or a grouprepresented by --NR²⁸ R²⁹ or --SO₂ NR³⁰ R³¹ wherein each of R²⁸ and R²⁹is the same or different from each other and represents a hydrogen atom,a linear or branched chain alkyl group, an aralkyl group or an arylgroup, and each of R³⁰ and R³¹ is the same or different from each otherand represents a hydrogen atom, a linear or branched chain alkyl group,an aralkyl group or an aryl group.
 6. An inhibitory agent of glutamicacid toxicity containing an effective amount of adihydrophenazinecarboxylic acid derivative of the formula (III) setforth in claim 5.